Ceramide-Protein Interactions Modulate Ceramide-Associated Lipotoxic Cardiomyopathy
Summary: Lipotoxic cardiomyopathy (LCM) is characterized by abnormal myocardial accumulation of lipids, including ceramide; however, the contribution of ceramide to the etiology of LCM is unclear. Here, we investigated the association of ceramide metabolism and ceramide-interacting proteins (CIPs) i...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2018-03-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124718302158 |
| _version_ | 1811226221584842752 |
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| author | Stanley M. Walls Anthony Cammarato Dale A. Chatfield Karen Ocorr Greg L. Harris Rolf Bodmer |
| author_facet | Stanley M. Walls Anthony Cammarato Dale A. Chatfield Karen Ocorr Greg L. Harris Rolf Bodmer |
| author_sort | Stanley M. Walls |
| collection | DOAJ |
| description | Summary: Lipotoxic cardiomyopathy (LCM) is characterized by abnormal myocardial accumulation of lipids, including ceramide; however, the contribution of ceramide to the etiology of LCM is unclear. Here, we investigated the association of ceramide metabolism and ceramide-interacting proteins (CIPs) in LCM in the Drosophila heart model. We find that ceramide feeding or ceramide-elevating genetic manipulations are strongly associated with cardiac dilation and defects in contractility. High ceramide-associated LCM is prevented by inhibiting ceramide synthesis, establishing a robust model of direct ceramide-associated LCM, corroborating previous indirect evidence in mammals. We identified several CIPs from mouse heart and Drosophila extracts, including caspase activator Annexin-X, myosin chaperone Unc-45, and lipogenic enzyme FASN1, and remarkably, their cardiac-specific manipulation can prevent LCM. Collectively, these data suggest that high ceramide-associated lipotoxicity is mediated, in part, through altering caspase activation, sarcomeric maintenance, and lipogenesis, thus providing evidence for conserved mechanisms in LCM pathogenesis in mammals. : Lipotoxic cardiomyopathy (LCM) is characterized by abnormal myocardial accumulation of lipids, including ceramide. Here, Walls et al. find that ceramide feeding or ceramide-elevating genetic manipulations induce LCM. They identified several ceramide-interacting proteins, whose subsequent cardiac-specific manipulation can prevent LCM by altering caspase activation, sarcomeric maintenance, and lipogenesis. Keywords: heart, sphingolipids, Drosophila, diabetic cardiac disease, myriocin, apoptosis, lipogenesis, Unc-45, Annexin, FASN |
| first_indexed | 2024-04-12T09:21:09Z |
| format | Article |
| id | doaj.art-10ae5f7e96514d399df5ec4f1b558f61 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-12T09:21:09Z |
| publishDate | 2018-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-10ae5f7e96514d399df5ec4f1b558f612022-12-22T03:38:38ZengElsevierCell Reports2211-12472018-03-01221027022715Ceramide-Protein Interactions Modulate Ceramide-Associated Lipotoxic CardiomyopathyStanley M. Walls0Anthony Cammarato1Dale A. Chatfield2Karen Ocorr3Greg L. Harris4Rolf Bodmer5Development, Aging and Regeneration Program, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA, USA; Department of Cellular and Molecular Biology, San Diego State University, San Diego, CA, USADevelopment, Aging and Regeneration Program, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA, USADepartment of Cellular and Molecular Biology, San Diego State University, San Diego, CA, USADevelopment, Aging and Regeneration Program, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA, USADepartment of Cellular and Molecular Biology, San Diego State University, San Diego, CA, USA; Corresponding authorDevelopment, Aging and Regeneration Program, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA, USA; Corresponding authorSummary: Lipotoxic cardiomyopathy (LCM) is characterized by abnormal myocardial accumulation of lipids, including ceramide; however, the contribution of ceramide to the etiology of LCM is unclear. Here, we investigated the association of ceramide metabolism and ceramide-interacting proteins (CIPs) in LCM in the Drosophila heart model. We find that ceramide feeding or ceramide-elevating genetic manipulations are strongly associated with cardiac dilation and defects in contractility. High ceramide-associated LCM is prevented by inhibiting ceramide synthesis, establishing a robust model of direct ceramide-associated LCM, corroborating previous indirect evidence in mammals. We identified several CIPs from mouse heart and Drosophila extracts, including caspase activator Annexin-X, myosin chaperone Unc-45, and lipogenic enzyme FASN1, and remarkably, their cardiac-specific manipulation can prevent LCM. Collectively, these data suggest that high ceramide-associated lipotoxicity is mediated, in part, through altering caspase activation, sarcomeric maintenance, and lipogenesis, thus providing evidence for conserved mechanisms in LCM pathogenesis in mammals. : Lipotoxic cardiomyopathy (LCM) is characterized by abnormal myocardial accumulation of lipids, including ceramide. Here, Walls et al. find that ceramide feeding or ceramide-elevating genetic manipulations induce LCM. They identified several ceramide-interacting proteins, whose subsequent cardiac-specific manipulation can prevent LCM by altering caspase activation, sarcomeric maintenance, and lipogenesis. Keywords: heart, sphingolipids, Drosophila, diabetic cardiac disease, myriocin, apoptosis, lipogenesis, Unc-45, Annexin, FASNhttp://www.sciencedirect.com/science/article/pii/S2211124718302158 |
| spellingShingle | Stanley M. Walls Anthony Cammarato Dale A. Chatfield Karen Ocorr Greg L. Harris Rolf Bodmer Ceramide-Protein Interactions Modulate Ceramide-Associated Lipotoxic Cardiomyopathy Cell Reports |
| title | Ceramide-Protein Interactions Modulate Ceramide-Associated Lipotoxic Cardiomyopathy |
| title_full | Ceramide-Protein Interactions Modulate Ceramide-Associated Lipotoxic Cardiomyopathy |
| title_fullStr | Ceramide-Protein Interactions Modulate Ceramide-Associated Lipotoxic Cardiomyopathy |
| title_full_unstemmed | Ceramide-Protein Interactions Modulate Ceramide-Associated Lipotoxic Cardiomyopathy |
| title_short | Ceramide-Protein Interactions Modulate Ceramide-Associated Lipotoxic Cardiomyopathy |
| title_sort | ceramide protein interactions modulate ceramide associated lipotoxic cardiomyopathy |
| url | http://www.sciencedirect.com/science/article/pii/S2211124718302158 |
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